Methods and compositions for treating autoimmune diseases
Disclosed are methods and compositions relating to the treatment of autoimmune diseases using anti-CD45 antibody drug conjugates (ADCs).
1. A method of depleting a population of CD45+ cells in a human patient having an autoimmune disease, the method comprising administering to the patient having the autoimmune disease an effective amount of an antibody-drug conjugate (ADC) comprising an anti-CD45 antibody, or antigen binding portion thereof, conjugated to a cytotoxin via a linker,
wherein the cytotoxin is a pyrrolobenzodiazepine dimer, or an indolinobenzodiazepine pseudodimer, wherein:
i) the pyrrolobenzodiazepine dimer has a structure of formula:
wherein the wavy line indicates the attachment point of the linker; or
ii) the indolinobenzodiazepine pseudodimer has a structure of formula:
wherein the wavy line indicates the attachment point of the linker.
2. A method of conditioning a human patient having an autoimmune disease for receiving a hematopoietic stem cell (HSC) transplant, the method comprising administering to the human patient having the autoimmune disease an antibody-drug conjugate (ADC) comprising an anti-CD45 antibody, or antigen binding portion thereof, conjugated to a cytotoxin via a linker,
wherein the cytotoxin is a pyrrolobenzodiazepine dimer, or an indolinobenzodiazepine pseudodimer, wherein:
i) the pyrrolobenzodiazepine dimer has a structure of formula:
wherein the wavy line indicates the attachment point of the linker; or
ii) the indolinobenzodiazepine pseudodimer has a structure of formula:
wherein the wavy line indicates the attachment point of the linker.
3. The method of claim 1 , wherein the autoimmune disease is an inflammatory arthritis, autoimmune encephalitis, scleroderma, multiple sclerosis, type 1 diabetes, or systemic sclerosis.
4. The method of claim 2 , further comprising administering a transplant comprising hematopoietic stem cells (HSCs) to the patient.
5. The method of claim 4 , wherein the HSC transplant is an autologous HSC transplant (autoHSCT).
6. The method of claim 4 , wherein the anti-CD45 ADC is administered to the patient about three days prior to the patient receiving the transplant comprising HSCs.
7. The method of claim 4 , wherein the HSC transplant is administered to the patient after the anti-CD45 ADC has substantially cleared from the blood of the human patient.
8. A method of treating a patient having scleroderma or multiple sclerosis, said method comprising administering an anti-CD45 antibody drug conjugate (ADC) to a patient having a sclerodermatous graft-vs-host disease (scGVHD), such that the scGVHD is treated, wherein the anti-CD45 ADC comprises an anti-CD45 antibody, or fragment thereof, conjugated to a cytotoxin via a linker;
wherein the cytotoxin is a pyrrolobenzodiazepine dimer, or an indolinobenzodiazepine pseudodimer, wherein:
i) the pyrrolobenzodiazepine dimer has a structure of formula:
wherein the wavy line indicates the attachment point of the linker; or
ii) the indolinobenzodiazepine pseudodimer has a structure of formula:
wherein the wavy line indicates the attachment point of the linker.
9. The method of claim 1 , wherein the anti-CD45 ADC is administered to the patient as a single dose or as a fractionated dose.
10. The method of claim 2 , wherein the patient does not require treatment for the autoimmune disease following the HSC transplant.
11. The method of claim 2 , wherein the patient has multiple sclerosis, and wherein the patient does not require treatment with natalizumab, dimethyl fumarate, or monomethyl fumarate following the HSC transplant.
12. The method of claim 2 , wherein the patient has arthritis, and wherein the patient does not require treatment with a Tumor Necrosis Factor (TNF) inhibitor following the HSC transplant.
13. The method of claim 12 , wherein the TNF inhibitor is an anti-Tumor Necrosis Factor-alpha (TNFα) antibody.
14. The method of claim 2 , wherein the patient enters a remission for at least 1 year following the HSC transplant.
15. The method of claim 14 , wherein the remission is clinical remission, biochemical remission, or histologic remission.
16. The method of claim 1 , wherein the anti-CD45 antibody is a chimeric antibody or a humanized antibody.
17. The method of claim 1 , wherein the anti-CD45 antibody is a human antibody.
18. The method of claim 1 , wherein the anti-CD45 antibody is intact.
19. The method claim 1 , wherein the anti-CD45 antibody or antigen-binding portion thereof is selected from the group consisting of a monoclonal antibody or antigen-binding portion thereof, a bispecific antibody or antigen-binding portion thereof, a dual-variable immunoglobulin domain, a single-chain Fv molecule (scFv), a diabody, a triabody, a nanobody, an antibody-like protein scaffold, a Fv fragment, a Fab fragment, a F(ab′)2 molecule, and a tandem di-scFv.
20. The method of claim 1 , wherein the anti-CD45 antibody has an isotype selected from the group consisting of IgG, IgA, IgM, IgD, and IgE.
21. The method of claim 20 , wherein the anti-CD45 antibody contains a human IgG1, IgG2, IgG3, or IgG4 isotype Fc domain.
22. The method of claim 1 , wherein the anti-CD45 antibody, or antigen binding portion thereof, comprises an Fc domain, and wherein the anti-CD45 antibody, or antigen binding portion thereof, is conjugated to the cytotoxin by way of a cysteine residue in the Fc domain.
23. The method of claim 22 , wherein the cysteine residue is introduced by way of an amino acid substitution in the Fc domain.
24. The method of claim 23 , wherein the amino acid substitution is D265C (EU numbering).